Describing and Explaining ADPKD Variability Within Families.
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ABSTRACT:
SUBMITTER: Achi SS
PROVIDER: S-EPMC10927945 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Publications
Describing and Explaining ADPKD Variability Within Families.
Achi Sai Santhoshini SS Mallett Andrew J AJ
Kidney international reports 20240130 3
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Project description:IntroductionDiscordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD.MethodsThe extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients.ResultsBased on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types.ConclusionExtreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD.
| S-EPMC6611955 | biostudies-literature
Project description:Background: Our study aims to comment on all ADPKD variants identified in our health area and explain how they are distributed geographically, to identify new variants, and relate the more frequent variants with their renal phenotype in terms of kidney survival. Materials and Methods: We identified patients suffering from ADPKD in a specialized consultation unit; genealogical trees were constructed from the proband. According to the ultrasound-defined modified Ravine-Pei criteria, relatives classified as at risk were offered participation in the genetic study. Socio-demographic, clinical, and genetic factors related to the impact of the variant on the survival of the kidney and the patient, such as age at RRT beginning and age of death, were recorded. Results: In 37 families, 33 new variants of the PKD1 gene were identified, which probably produce a truncated protein. These variants included 2 large deletions, 19 frameshifts, and 12 stop-codons, all of which had not been previously described in the databases. In 10 families, six new probably pathogenic variants in the PKD2 gene were identified. These included three substitutions; two deletions, one of which was intronic and not associated with any family; and one duplication. A total of 11 missense variants in the PKD1 gene were grouped in 14 families and classified as probably pathogenic. We found that 33 VUS were grouped into 18 families and were not described in the databases, while another 15 were without grouping, and there was only 1 in the PKD2 gene. Some of these variants were present in patients with a different pathogenic variant (described or not), and the variant was probably benign. Renal survival curves were compared to nonsense versus missense variants on the PKD1 gene to check if there were any differences. A group of 328 patients with a nonsense variant was compared with a group of 264 with a missense variant; mean renal survival for truncated variants was lower (53.1 ± 0.46 years versus non-truncated variant 59.1 ± 1.36 years; Log Rank, Breslow, and Tarone Ware, p < 0.05). Conclusions: To learn more about ADPKD, it is necessary to understand genetics. By describing new genetic variants, we are approaching creation of an accurate genetic map of the disease in our country, which could have prognostic and therapeutic implications in the future.
| S-EPMC10971467 | biostudies-literature
Project description:Numerous studies have shown that fertility behavior is spatially clustered. In addition to pure contextual effects, two causal mechanisms could drive this pattern. First, neighbors may influence each other's fertility and second, family size may influence decisions about where to live. In this study we examine these two potential causal mechanisms empirically, using the sex composition of the two eldest children and twin births as instrumental variables (IVs) for having a third child. We estimate how having a third child affects three separate outcomes: the fertility of neighbors; the propensity to move houses; and the likelihood of living in a family-friendly neighborhood with many children. We draw residential and childbearing histories (2000-2018) from Norwegian administrative registers (N ~ 167,000 women). Individuals' neighborhoods are defined using time-varying geocoordinates for place of residence. We identify selective moves as one plausible causal driver of residential clustering of large families. This study contributes to the understanding of fertility and relocation, and to the literature on the social interaction effects of fertility, by testing the relevance of yet another network: that of neighbors.
| S-EPMC10115922 | biostudies-literature
Project description:For a quarter of a century researchers have been documenting and trying to explain trends in Americans' vocabulary knowledge using data from the General Social Survey (GSS) and its WORDSUM test. Trends in Americans' vocabulary knowledge have important practical implications-for example, for educational policy and practice-and speak to the American workforce's competitiveness in the global knowledge economy. We contribute to this debate by analyzing 1978-2018 GSS data using an improved analytical approach that is consistent with theoretical notions of cohort effects and that permits simultaneously estimating inter-cohort average differences and intra-cohort life-course changes. We find that WORDSUM scores peak around age 35 and gradually decline in older ages; the scores were significantly lower in the 1980s and higher in the late 2000s and 2010s; and the 1940-1954 birth cohorts and the 1965 and later birth cohorts had notably higher and lower scores, respectively, than the expectation based on age and period main effects. We provide new evidence that such cohort differences tend to persist over the life course. Interestingly, the effects of increasing educational attainment and decreasing reading behaviors seemed to cancel out, leading to a relatively flat overall period trend. Trends in television viewing and word obsolescence did not appear to affect age, period, or cohort trends in WORDSUM scores.Supplementary informationThe online version contains supplementary material available at 10.1007/s11113-023-09771-5.
| S-EPMC10119018 | biostudies-literature
Project description:Intrinsically disordered regions in eukaryotic proteomes contain key signaling and regulatory modules and mediate interactions with many proteins. Many viral proteomes encode disordered proteins and modulate host factors through the use of short linear motifs (SLiMs) embedded within disordered regions. However, the degree of viral protein disorder across different viruses is not well understood, so we set out to establish the constraints acting on viruses, in terms of their use of disordered protein regions. We surveyed predicted disorder across 2,278 available viral genomes in 41 families, and correlated the extent of disorder with genome size and other factors. Protein disorder varies strikingly between viral families (from 2.9% to 23.1% of residues), and also within families. However, this substantial variation did not follow the established trend among their hosts, with increasing disorder seen across eubacterial, archaebacterial, protists, and multicellular eukaryotes. For example, among large mammalian viruses, poxviruses and herpesviruses showed markedly differing disorder (5.6% and 17.9%, respectively). Viral families with smaller genome sizes have more disorder within each of five main viral types (ssDNA, dsDNA, ssRNA+, dsRNA, retroviruses), except for negative single-stranded RNA viruses, where disorder increased with genome size. However, surveying over all viruses, which compares tiny and enormous viruses over a much bigger range of genome sizes, there is no strong association of genome size with protein disorder. We conclude that there is extensive variation in the disorder content of viral proteomes. While a proportion of this may relate to base composition, to extent of gene overlap, and to genome size within viral types, there remain important additional family and virus-specific effects. Differing disorder strategies are likely to impact on how different viruses modulate host factors, and on how rapidly viruses can evolve novel instances of SLiMs subverting host functions, such as innate and acquired immunity.
| S-EPMC3631256 | biostudies-literature
Project description:IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity.MethodsTo better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity.ResultsMarked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001).ConclusionUsing objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.
| S-EPMC10928004 | biostudies-literature
Project description:Proteins play a central role in biological processes, and understanding their conformational variability is crucial for unraveling their functional mechanisms. Recent advancements in high-throughput technologies have enhanced our knowledge of protein structures, yet predicting their multiple conformational states and motions remains challenging. This study introduces Dimensionality Analysis for protein Conformational Exploration (DANCE) for a systematic and comprehensive description of protein families conformational variability. DANCE accommodates both experimental and predicted structures. It is suitable for analysing anything from single proteins to superfamilies. Employing it, we clustered all experimentally resolved protein structures available in the Protein Data Bank into conformational collections and characterized them as sets of linear motions. The resource facilitates access and exploitation of the multiple states adopted by a protein and its homologs. Beyond descriptive analysis, we assessed classical dimensionality reduction techniques for sampling unseen states on a representative benchmark. This work improves our understanding of how proteins deform to perform their functions and opens ways to a standardised evaluation of methods designed to sample and generate protein conformations.
| S-EPMC11237097 | biostudies-literature
Project description:In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing.The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells.The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.
| S-EPMC2553322 | biostudies-literature
Project description:Contamination of responses due to extreme and midpoint response style can confound the interpretation of scores, threatening the validity of inferences made from survey responses. This study incorporated person-level covariates in the multidimensional item response tree model to explain heterogeneity in response style. We include an empirical example and two simulation studies to support the use and interpretation of the model: parameter recovery using Markov chain Monte Carlo (MCMC) estimation and performance of the model under conditions with and without response styles present. Item intercepts mean bias and root mean square error were small at all sample sizes. Item discrimination mean bias and root mean square error were also small but tended to be smaller when covariates were unrelated to, or had a weak relationship with, the latent traits. Item and regression parameters are estimated with sufficient accuracy when sample sizes are greater than approximately 1,000 and MCMC estimation with the Gibbs sampler is used. The empirical example uses the National Longitudinal Study of Adolescent to Adult Health's sexual knowledge scale. Meaningful predictors associated with high levels of extreme response latent trait included being non-White, being male, and having high levels of parental support and relationships. Meaningful predictors associated with high levels of the midpoint response latent trait included having low levels of parental support and relationships. Item-level covariates indicate the response style pseudo-items were less easy to endorse for self-oriented items, whereas the trait of interest pseudo-items were easier to endorse for self-oriented items.
| S-EPMC8243201 | biostudies-literature
Project description:PurposeOptimal ciclosporin A (CsA) exposure in kidney transplant recipients is difficult to attain because of variability in CsA pharmacokinetics. A better understanding of the variability in CsA exposure could be a good means of individualizing therapy. Specifically, genetic variability in genes involved in CsA metabolism could explain exposure differences. Therefore, this study is aimed at identifying a relationship between genetic polymorphisms and the variability in CsA exposure, while accounting for non-genetic sources of variability.MethodsDe novo kidney transplant patients (n = 33) were treated with CsA for 1 year and extensive blood sampling was performed on multiple occasions throughout the year. The effects of the non-genetic covariates hematocrit, serum albumin concentration, cholesterol, demographics (i.e., body weight), CsA dose interval, prednisolone dose and genetic polymorphisms in genes encoding ABCB1, CYP3A4, CYP3A5, and PXR on CsA pharmacokinetics were studied using non-linear mixed effect modeling.ResultsThe pharmacokinetics of CsA were described by a two-compartment disposition model with delayed absorption. Body weight was identified as the most important covariate and explained 35% of the random inter-individual variability in CsA clearance. Moreover, concurrent prednisolone use at a dosage of 20 mg/day or higher was associated with a 22% higher clearance of CsA, hence lower CsA exposure. In contrast, no considerable genotype effects (i.e., greater than 30-50%) on CsA clearance were found for the selected genes.ConclusionsIt appears that the selected genetic markers explain variability in CsA exposure insufficiently to be of clinical relevance. Therefore, therapeutic drug monitoring is still required to optimize CsA exposure after administration of individualized doses based on body weight and, as this study suggests, co-administration of prednisolone.
| S-EPMC2868991 | biostudies-literature